(a) Field of the Invention
The present invention relates to a biodegradable and thermosensitive poly(organophosphazene) having a functional group and showing sol-gel phase transition depending on temperature change, a preparation method thereof, and a use thereof for delivery of bioactive substances.
(b) Description of the Related Art
An aqueous solution of a thermosensitive polymer hydrogel can maintain a sol-phase at a low temperature, and can be changed into a gel-phase by raising the temperature. Such sol-gel phase transition can occur reversibly. A thermosensitive polymer hydrogel has been considered as a useful delivery material of drugs for injection due to its advantage that the aqueous solution thereof can be easily mixed with therapeutic drugs. Therefore, it can be easily injected into a living body without any surgical operation, and when injected into a desired region of a living body, it forms a gel-phase with a three-dimensional structure at body temperature and is thereby capable of controlled and sustained release of a drug (Nature, 388, 860 (1997), and U.S. Pat. No. 6,201,072).
However, when such thermosensitive polymer hydrogel is used as a delivery material of a drug for injection, there is a problem in that drugs with small molecular weights or high hydrophilicity can easily and rapidly pass through the three-dimensional network structure of the gel formed by the thermosensitive polymer hydrogel, causing a large amount (30% or more) of the drugs to be released at an early stage of injection. Further, there is another problem in that the release of the drug is completed in a short time due to a high rate of diffusion of a hydrophilic drug from the gel into the living body, whereby a sustained release of the drug cannot be achieved (Adv Drug Deliv Rev, 31, 197 (1998)).
In order to solve such problems, various thermosensitive polymer hydrogels with a functional group that is capable of directly binding to drugs have been developed. When the thermosensitive polymer hydrogel is injected into a living body together with a hydrophilic drug chemically binding thereto through the functional group, the drug is released by degradation of the polymer or breakage of the chemical bond between the polymer and the drug, thereby achieving a sustained release.
It has been attempted to bind N-isopropylacrylamide, which is an exemplary thermosensitive polymer, an acrylic acid copolymer that acts as a functional group, and a hydrophilic drug through a direct chemical bond. However, there is still a problem in that the N-isopropylacrylamide and the acrylic acid copolymer, which bind with the drug, are cytotoxic and non-biodegradable (Macromolecules, 34, 8569, 2001). Polyethylene oxide-polylacticglycolic acid-polyethylene oxide (PEO-PLGA-PEO, Regel) is an exemplary thermosensitive polymer hydrogel that is biodegradable in a living body. However, since the PEO-PLGA-PEO polymer has no functional group, it is not able to bind with hydrophilic drugs. It has also been considered to chemically bind hydrophilic drugs to chitosan with a functional group to form another biodegradable and thermosensitive polymer hydrogel. However, there are still some problems in that it is difficult for chitosan to form a strong chemical bond with hydrophilic drugs due to its insolubility in an organic solvent, and it has a slow gelation rate and low gel solidity, which is undesirable for use as a delivery material of drugs.
The present inventors have reported that poly(organophosphazene) prepared by substitution with an amino acid ester and methoxypolyethyleneglycol in a linear dichlorophosphazene molecule show thermosensitivity that has a sol-phase in an aqueous solution at a specific temperature or lower, and a phase transition from the sol-phase to the gel-phase of a three-dimensional structure occurs when raising the temperature above the specific temperature. Further, they are gradually hydrolyzed in an aqueous solution [Macromolecules 32, 2188 (1999); Macromolecules 32, 7820 (1999); Macromolecules 35, 3876 (2002); Korean Patent Nos. 259,367 and 315,630; and U.S. Pat. No. 6,319,984].
However, the poly(organophosphazene) disclosed in the above documents have a limitation in being applied as a delivery material of hydrophilic drugs since they have no functional group. Therefore, in order to solve the above problems, it is required to develop a novel poly(organophosphazene) that shows a sol-gel phase transition depending on a change of temperature and that has a functional group that is capable of binding with bioactive substances.